1. Field of the Invention
The present invention relates generally to the fields of surgery, cancer and histopathology. More particularly, it concerns a method for identification and labeling of sentinel lymph nodes as part of the prognostic and diagnostic evaluation of cancer. In particular aspects, the present invention relates to use of a molecular markers, optionally in conjunction with dyes/tracers, to identify and label sentinel lymph nodes in cancers such as breast cancer, gastrointestinal cancers and melanoma.
2. Description of Related Art
The technique of intraoperative lymphatic mapping and sentinel lymph node (SLN) dissection has revolutionized the management of regional tumor-draining lymph nodes in melanoma and other solid cancers that metastasize via the lymphatics. The procedure is minimally invasive and reduces morbidity. Furthermore, this approach provides for a more focused assessment of occult metastasis in a cost-effective manner, which may improve clinicopathological staging. Since Morton et al. (1992) introduced the technique in melanoma, it has been successfully applied to breast cancer (Giuliano et al., 1994; Giuliano et al., 1995), colon cancer (Saha et al., 2000; Bilchik et al., 1998), thyroid cancer (Kelemen et al., 1998), gastric cancer (Kitagawa et al., 2000), head & neck cancer (Shoaib et al., 1999), lung cancer (Liptay et al., 2002) and prostate cancer (Wawroschek et al., 2001).
Because the SLN is the first lymph node to harbor metastatic cancer cells from the primary tumor, its tumor status is highly predictive of the histopathology of the associated lymphatic drainage basin. It has been shown that patients who have tumor-free SLN do not need a complete lymph node dissection, thus avoiding the cost and potential morbidity associated with a formal elective lymph node dissection (Morton et al., 1992; Kitagawa et al., 2000; Tsioulias et al., 2000; Giuliano et al., 1997; Brobeil et al., 1999). The clinical benefits of SLN dissection are currently being assessed in several large ongoing multicenter randomized trials for melanoma, breast and colon cancer (Veronesi et al., 1997; Giuliano et al., 2000; Morton et al., 1999; Haigh and Giuliano, 2000; Harlow and Krag, 2001; Bilchik et al., 2001).
Concurrent with the development of the SLN procedure in the 1990's, the inventors' laboratory has been developing molecular detection approaches to improve identification of occult metastatic tumor cells in the SLN(s) of melanoma, breast cancer, and colon cancer patients (Bilchik et al., 2001; Hoon et al., 1996; Bostick et al., 1998a; Bostick et al., 1998b; Bostick et al., 1999b; Wascher et al., 2001). The inventors have shown in frozen sections of SLN, using multimarker RT-PCR assays, that melanoma, colon and breast cancer patients can be upstaged compared to H&E and IHC analysis (Bilchik et al., 2001; Bostick et al., 1998a; Bostick et al., 1999b). More recently, through extensive studies, it has become known that IHC detection for micrometastasis and occult tumor cells in the SLN is more efficient if carried out on paraffin-embedded sections compared to frozen sections. This approach also minimizes the variability of analysis among institutes. Studies in the inventors' laboratory have evolved to assess for metastatic tumor cells in paraffin-embedded SLN.
Although the SLN is highly predictive of the histologic status of the tumor-draining lymph node basin when using the technique of blue dye and/or radioisotopes for detection, the ability of these reagents to accurately categorize draining lymph node hierarchy is limited. This is particularly true when multiple lymph nodes may stain blue and/or demonstrate radioactivity. Additionally, because these substances dissolve and decay respectively over time, they lack utility as an enduring label of the sentinel node, as well as additional lymph nodes for subsequent analysis of paraffin-embedded tissues. Introduction of a durable substrate marker during surgical lymphatic mapping, which can be readily quantitated among the tumor-draining lymph nodes, would provide a unique method to accurately label the sentinel and secondary lymph nodes during the entire course of their evaluation.